The first specific aim is based on preliminary data that indicates that the MEK inhibitor U0126 reduces ERK-1/2 activity, induces mesenchymal apoptosis, and dramatically inhibits branching morphogenesis in fetal lung explants. To demonstrate that ERK-1/2 signaling plays a critical role in fibroblast apoptosis and lung development/branching morphogenesis I propose to rescue ERK-1/2 signaling with an adenoviral construct encoding the a constitutively activated MEK gene. The second specific aim is based on my preliminary data in which I have shown that ERK-3 expression is developmentally regulated during fetal lung development and is expressed in the P19 embryonic carcinoma cell line. I will try to determine the role of ERK-3 in development by cloning the ERK-3 gene into an adenoviral vector and both inhibiting and over expressing the ERK-3 gene in fetal lung explants and P19 cells. The third specific aim will examine the mechanism of nitrofen-induced apoptosis and pulmonary hypoplasia and the mechanisms of antioxidant rescue of nitrofen-induced pulmonary hypoplasia.